rs3807153

Positions:

chr7-138733046-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020632.3(ATP6V0A4):c.1739T>C(p.Met580Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,613,950 control chromosomes in the GnomAD database, including 3,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 1002 hom., cov: 31)

Exomes 𝑓: 0.056 ( 2997 hom. )

Consequence

ATP6V0A4
NM_020632.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

ATP6V0A4 (HGNC:866): (ATPase H+ transporting V0 subunit a4) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. This gene is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing. [provided by RefSeq, Jul 2008]

ATP6V0A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022696257).

BP6

Variant 7-138733046-A-G is Benign according to our data. Variant chr7-138733046-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 5154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-138733046-A-G is described in Lovd as [Benign]. Variant chr7-138733046-A-G is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6V0A4	NM_020632.3 linkuse as main transcript	c.1739T>C	p.Met580Thr	missense_variant	17/22	ENST00000310018.7	NP_065683.2	Q9HBG4A0A024R791
ATP6V0A4	NM_130840.3 linkuse as main transcript	c.1739T>C	p.Met580Thr	missense_variant	16/21		NP_570855.2	Q9HBG4A0A024R791
ATP6V0A4	NM_130841.3 linkuse as main transcript	c.1739T>C	p.Met580Thr	missense_variant	16/21		NP_570856.2	Q9HBG4A0A024R791

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP6V0A4	ENST00000310018.7 linkuse as main transcript	c.1739T>C	p.Met580Thr	missense_variant	17/22	1	NM_020632.3	ENSP00000308122.2		Q9HBG4

Frequencies

GnomAD3 genomes

AF:

0.0908

AC:

13799

AN:

152026

Hom.:

992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0554

Gnomad ASJ

AF:

0.0985

Gnomad EAS

AF:

0.0560

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0365

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0455

Gnomad OTH

AF:

0.0900

GnomAD3 exomes

AF:

0.0658

AC:

16551

AN:

251412

Hom.:

819

AF XY:

0.0666

AC XY:

9043

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.0376

Gnomad ASJ exome

AF:

0.0939

Gnomad EAS exome

AF:

0.0546

Gnomad SAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.0371

Gnomad NFE exome

AF:

0.0458

Gnomad OTH exome

AF:

0.0601

GnomAD4 exome

AF:

0.0559

AC:

81714

AN:

1461806

Hom.:

2997

Cov.:

AF XY:

0.0571

AC XY:

41515

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.192

Gnomad4 AMR exome

AF:

0.0397

Gnomad4 ASJ exome

AF:

0.0926

Gnomad4 EAS exome

AF:

0.0679

Gnomad4 SAS exome

AF:

0.119

Gnomad4 FIN exome

AF:

0.0366

Gnomad4 NFE exome

AF:

0.0464

Gnomad4 OTH exome

AF:

0.0672

GnomAD4 genome

AF:

0.0910

AC:

13851

AN:

152144

Hom.:

1002

Cov.:

AF XY:

0.0908

AC XY:

6756

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.194

Gnomad4 AMR

AF:

0.0554

Gnomad4 ASJ

AF:

0.0985

Gnomad4 EAS

AF:

0.0559

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.0365

Gnomad4 NFE

AF:

0.0455

Gnomad4 OTH

AF:

0.0942

Alfa

AF:

0.0577

Hom.:

882

Bravo

AF:

0.0959

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0496

AC:

191

ESP6500AA

AF:

0.185

AC:

817

ESP6500EA

AF:

0.0479

AC:

412

ExAC

AF:

0.0691

AC:

8390

Asia WGS

AF:

0.137

AC:

476

AN:

3478

EpiCase

AF:

0.0478

EpiControl

AF:

0.0468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 16611712, 27884173, 10973252, 20981092, 24252324) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Autosomal recessive distal renal tubular acidosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 25, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;D;D;.;.;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;.;D;D;.

MetaRNN

Benign

0.0023

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.0

M;M;M;.;.;M

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

D;D;.;.;.;D

REVEL

Pathogenic

0.65

Sift

Benign

0.032

D;D;.;.;.;D

Sift4G

Uncertain

0.040

D;D;.;.;.;D

Polyphen

0.77

P;P;P;.;.;P

Vest4

0.26

MPC

0.41

ClinPred

0.051

GERP RS

5.8

Varity_R

0.42

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over